Biochemical correlates of the differential sensitivity of subtypes of human leukemia to deoxyadenosine and deoxycoformycin

Leukemic cells incubated in vitro with 2'-deoxyadenosine (dAdo) plus an inhibitor of adenosine deaminase, 2'-deoxycoformycin (DCF), show different metabolic responses depending on the histologic and immunologic type of the leukemia. Leukemic cells were obtained from 54 patients with acute lymphoblastic leukemia (ALL), 9 with myeloid or nonlymphoblastic leukemia, 3 with chronic lymphocytic leukemia (CLL), and 3 with lymphoma. There was a wide variation in the LD₅₀, the incorporation of dAdo that caused 50% inhibition of the incorporation of ³H-thymidine into cells in the presence of 20 μM DCF. T-cell leukemia specimens were much more sensitive to dAdo than were specimens of pre-B-ALL and null-ALL. In leukemic cells that had been incubated with ¹⁴C-dAdo plus DCF, a good correlation was observed between the LD₅₀ and the ratio of ¹⁴C-deoxyATP to ATP (correlation coefficient for the fit to a hyperbola = 0.853). The acumulation of deoxyATP by the leukemic cell specimens was correlated best with the activity of ecto-ATPase, less well with cytoplasmic 5'-nucleotidase and deoxyadenosine kinase, and poorly with adenosine deaminase and ecto-5'-nucleotidase. The clinical response to DCF therapy of a patient with T-ALL and another with pre-B-ALL was consistent with the in vitro metabolic response of their cells to DCF and dAdo.